1. Field of the Invention
The invention relates to the synthesis of tetrahydroquinoline derivatives and their use in the treatment of various carcinomas.
2. General Background of the Invention
U.S. Pat. No. 6,077,862, incorporated herein by reference, provides an excellent background for the cancer chemotherapeutic use of the this invention.
Chemotherapeutic approaches are most effective to fight cancers with large growth factors, i.e., ones whose cells are rapidly dividing. Ideally cytotoxic agents that have specificity to recognize certain cancer and tumor cells while not affecting normal cells or other less malign tumor cells would be extremely desirable. Unfortunately, none have been found and instead agents that target especially rapidly dividing cells (both tumor and normal) have been generally used.
Clearly, the development of agents that would target certain cancer cells due to some unique specificity for them would be a breakthrough.
Tetrahydroquinoline moiety is present in various natural products and many tetrahydroquinoline derivatives bearing simple or complex substituents exhibit a broad range of biological activities[1] Therefore, it has been attracted researchers continuously to develop methods for the synthesis of tetrahydroquinoline derivatives.[2] Among the various methods, Lewis acid catalyzed aza-Diels-Alder reaction of N-arylimines with various dienophiles is one of the most powerful tools for constructing 2,3,4-substituted tetrahydroquinoline derivatives.[3] When cyclic enol ethers, such as 2,3-dihydrofuran or 3,4-dihydro-2H-pyran, are employed as dienophiles, tricyclic compounds (furano or pyrano quinoline derivatives) are obtained.[4] A one-pot procedure for synthesizing such compounds, based on the three components reaction of a substituted aniline, an aryl aldehyde and an electron-rich olefin in the presence of Lewis acid catalysts, has been reported recently.[5] Since this reaction is much efficient with aryl-aldimines than with alkyl-aldimines, various 2-aryl-tetrahydroquinolines have been synthesized and only a few examples of 2-substituted tetrahydroquinoline derivatives were reported. No procedure was available to synthesize 2-substituted tetrahydroquinoline derivatives via a simple and direct coupling between an aniline derivative and a cyclic enol ether or a cyclic hemiacetal (or its equivalent).
Due to the above-mentioned problems in the art, the present inventors have sought improvements and provide such improvements herein.